JP2009514927A - Process for the preparation of leukotriene antagonists and intermediates thereof - Google Patents

Abstract

It includes a process for preparing montelukast from a novel intermediate compound of formula (VI) previously prepared by reacting the corresponding sulfonate with 1- (mercaptomethyl) cyclopropyl) methanol. Compound (VI) is reacted with a Grignard reagent to convert the ester group to a tertiary alcohol, followed by the conversion of the primary alcohol to a sulfonate, substituting the sulfonate group with a cyano group, and finally a hydrolysis reaction. To change the cyano compound to a carboxylic acid compound to obtain montelukast. Montelukast can also be prepared by hydrolyzing the corresponding amide. Also included are novel intermediate compounds useful in such preparation methods.

Description

  The present invention relates to a process for the preparation of montelukast and some novel intermediates useful in such a process.

(Background technology)
Montelukast is 1-[[[(1R) -1- [3-[(1E) -2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-1- Methylethyl) phenyl] propyl] sulfanyl] methyl] cyclopropaneacetic acid, an international common name (INN name) with CAS number 158966-92-8. Montelukast monosodium salt (CAS number 151767-02-1) is used to treat asthma, inflammation, angina pectoris, cerebral spasm, glomerulonephritis, hepatitis, endotoxemia, uveitis, and allograft rejection. Currently used.

に相当する。
モンテルカスト及びその塩を調製するための種々の合成方法が知られている。ＥＰ４８０７１７には、モンテルカストナトリウム塩を含むある種の置換キノロン化合物、その調製方法、及びこれら化合物を使用する薬学的組成物が開示されている。モンテルカストナトリウムの幾つかの調製方法がこの文献に報告されている。実施例１６１がモンテルカストナトリウム塩の調製に関連している。この実施例によれば、モンテルカストナトリウム塩の調製は、その対応するメチルエステルを介して進行していき、その調製は、インサイツで生じる保護されたメシレート(２-(２-(２-(３(Ｓ)-(３-(２-(７-クロロ-２-キノリニル)-エテニル)フェニル)-３-(メタンスルホニルオキシ)プロピル)フェニル)-２-プロポキシ)テトラヒドロピランと、メチル-１-(メルカプトメチル)-シクロプロパンアセタートを、水素化ナトリウム又は炭酸セシウムの補助でカップリングさせることを含む。このようにして得られたメチルエステルを加水分解してモンテルカスト遊離酸とし、これをついでナトリウム塩に直接転換させる。この方法は、メチルエステル中間体及び／又は最終生成物の面倒なクロマトグラフィー精製を必要とし、中間体及び最終生成物の収率が低いことから、大規模生産には特に適していない。モンテルカストナトリウム塩を調製するための他の方法は、次の式：

のチオアセテートをヒドラジン又はアルコキシドと反応させ、続いて適切な１-置換シクロプロピルアセテートと反応させ、ついで第３級アルコールを脱保護して、モンテルカストを得ることを含む。 The structure of montelukast monosodium salt is represented by the following formula (I):

It corresponds to.
Various synthetic methods for preparing montelukast and its salts are known. EP 480717 discloses certain substituted quinolone compounds, including montelukast sodium salt, methods for their preparation, and pharmaceutical compositions using these compounds. Several methods for preparing montelukast sodium have been reported in this document. Example 161 relates to the preparation of montelukast sodium salt. According to this example, the preparation of montelukast sodium salt proceeds via its corresponding methyl ester, which preparation is a protected mesylate (2- (2- (2- (3 ( S)-(3- (2- (7-Chloro-2-quinolinyl) -ethenyl) phenyl) -3- (methanesulfonyloxy) propyl) phenyl) -2-propoxy) tetrahydropyran and methyl-1- (mercapto) Coupling of methyl) -cyclopropaneacetate with the aid of sodium hydride or cesium carbonate The methyl ester thus obtained is hydrolyzed to the montelukast free acid, which is then converted to the sodium salt. This method requires tedious chromatographic purification of the methyl ester intermediate and / or final product, resulting in low yields of intermediate and final product. . Since, not particularly suitable for large-scale production Another method for preparing montelukast sodium salt, the following formula:

Of thioacetate with hydrazine or alkoxide followed by reaction with a suitable 1-substituted cyclopropyl acetate followed by deprotection of the tertiary alcohol to obtain montelukast.

  EP 737186 relates to a process for the preparation of montelukast or a salt thereof, which comprises dilithium dianion of 1- (mercaptomethyl) cyclopropaneacetic acid with the corresponding mesylate alcohol ((2- (2- (2- (3 ( S)-(3- (2- (7-Chloro-2-quinolinyl) -ethenyl) phenyl) -3- (methanesulfonyloxy) propyl) phenyl) -2-propanol) to give montelukast to give dicyclohexylamine Further conversion to the corresponding sodium salt via a salt.

を有するチオ酢酸エステルをヨウ化メチルマグネシウムと反応させ、次の式

のチオアルコールを得ることを含む。 CN1422013A relates to a process for preparing montelukast or its sodium salt, which process has the formula

Is reacted with methylmagnesium iodide to produce the following formula:

To obtain a thioalcohol of

  Montelukast is synthesized by reacting the thiol alcohol intermediate described above with the appropriate 1-halo substituted cyclopropyl acetate, followed by hydrolysis of the ester group.

  US2005107612 describes a process for the preparation of montelukast or a salt thereof, which comprises 2- [1- [1-R-3- [2- (7 chloroquinolin-2-yl) vinyl [phenyl]- Reacting a late intermediate compound which is 3- [2-methoxycarbonylphenyl] propylsulfonylmethyl] cyclopropyl] acetic acid or a salt thereof with methylmagnesium chloride or methylmagnesium bromide.

  Finally, US 2005/0234241 describes 2- (2- (3 (S) -3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-sulfonyloxypropyl) phenyl) -2-propanol Disclosed is a method for preparing montelukast based on reacting 1- (mercaptomethyl) cyclopropaneacetonitrile or a salt of 1- (mercaptomethyl) cyclopropaneacetamide with subsequent hydrolysis using a base. .

  Although certain methods for preparing montelukast are known, a need still exists for new methods for preparing montelukast and its salts.

(Summary of Invention)
The inventors have discovered a novel and efficient method for preparing montelukast from a novel intermediate compound that proceeds in high yield and does not require chromatographic purification.

のモンテルカスト(Ｉ)、もしくはその製薬的に許容可能な塩、又は水和物を含むその溶媒和物の調製方法であって、
(ａ)式(ＩＶ)

（上式中、Ｒ_１は、(Ｃ_１-Ｃ_４)-アルキル、フェニル、及び(Ｃ_１-Ｃ_４)-アルキル基により一置換又は二置換されたフェニルから選択された基である）の化合物を、アルカリ金属シアン化物と反応させて、式(ＩＩＩ)

の化合物を得、該化合物(ＩＩＩ)を遊離塩基又はその塩として分離し；
(ｂ)場合によっては、工程(ａ)で得られた式(ＩＩＩ)の化合物を式(ＩＩ)

の化合物に至らしめる反応条件で加水分解し、反応媒体から該化合物(ＩＩ)を分離し；
(ｃ)工程(ａ)又は工程(ｂ)で得られた化合物に、モンテルカスト(Ｉ)に至らしめる反応条件で加水分解反応を施し；
(ｄ)場合によっては、製薬的に許容可能な塩基でモンテルカスト(Ｉ)を処理して、対応する塩を形成させる；
工程を含んでなる調製方法が提供される。 Thus, according to one aspect of the present invention,

A process for preparing montelukast (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof comprising a hydrate comprising:
(a) Formula (IV)

(Wherein R ₁ is a group selected from (C ₁ -C ₄ ) -alkyl, phenyl, and phenyl mono- or di-substituted by a (C ₁ -C ₄ ) -alkyl group) The compound is reacted with an alkali metal cyanide to give a compound of formula (III)

And the compound (III) is isolated as the free base or a salt thereof;
(b) In some cases, the compound of formula (III) obtained in step (a) is converted to formula (II)

Hydrolyzing under the reaction conditions leading to the compound, separating the compound (II) from the reaction medium;
(c) subjecting the compound obtained in step (a) or step (b) to a hydrolysis reaction under the reaction conditions leading to montelukast (I);
(d) optionally treating montelukast (I) with a pharmaceutically acceptable base to form the corresponding salt;
A method of preparation comprising the steps is provided.

のアルコールを、Ｒ_１が上述したものと同じ意味を有する式Ｃｌ-ＳＯ_２-Ｒ_１の塩化スルホニルと反応させて、式(ＩＶ)の化合物を得る。 In the above, in a further step of the preparation method, the formula (V)

Alcohol, R ₁ is reacted with a sulfonyl chloride of formula Cl-SO ₂ -R ₁ having the meanings given above, to give a compound of formula (IV).

の化合物を、メチルリチウム及びメチルマグネシウムハライドから選択されるグリニャール試薬と、場合によっては塩化セリウムの存在下で反応させて、遊離塩基又はその塩として分離可能な式(Ｖ)の化合物を得る。 In another further step, the formula (VI):

Is reacted with a Grignard reagent selected from methyllithium and methylmagnesium halide, optionally in the presence of cerium chloride, to give a compound of formula (V) which can be separated as the free base or a salt thereof.

In another further step, R ₂ is a group selected from (C ₁ -C ₄ ) -alkyl, phenyl, and phenyl mono- or di-substituted by a (C ₁ -C ₄ ) -alkyl group A compound of formula (VII) is reacted with a compound of formula (VIII) in the presence of a base selected from cesium carbonate, sodium hydroxide, and lithium-bis (trimethylsilyl) amide as the free base or salt thereof. A separable compound of formula (VI) is obtained.

  The compounds of formula (IV), (V) or salts thereof, the compound of formula (VI) or salts thereof described above are novel and are part of the present invention. Thus, another aspect of the present invention is to provide novel intermediate compounds for preparing montelukast, especially compounds of formula (IV), (V) and (VI). Salts of compound (V), especially citrates, salts of compound (VI), especially oxalates, and compounds of formula (III) and oxalic acid, L (-)-malic acid, L-(+)- Salts formed with tartaric acid, maleic acid, fumaric acid, succinic acid, benzoic acid, 4-hydroxymandelic acid, citric acid, benzenesulfonic acid, and mandelic acid form part of the present invention.

  The method of the present invention is particularly advantageous in practical industrial implementations because it is cost effective and suitable for scale-up. Unlike other known preparation methods of montelukast, this method avoids intramolecular cyclization of the intermediate compound. All intermediates are thus neatly formed and do not require chromatographic separation. Furthermore, the final product is obtained with high chemical and optical purity and high yield.

(Detailed description of the invention)
As mentioned above, cyano compounds of formula (III) as free base or salts thereof are obtained from sulfonates of formula (IV). Preferably, the compound of formula (III) is obtained as a free base from the compound of formula (IV). The conversion involves reacting compound (IV) with an alkali metal cyanide such as sodium or potassium cyanide in a suitable solvent such as dimethylformamide, dimethyl sulfoxide, ethyl acetate or acetonitrile at a temperature from 0 ° C. to reflux temperature. It is carried out by letting. Preferably the reaction is carried out at about 60 ° C. The reaction can be carried out in the presence of a phase transfer catalyst. Specific examples of suitable phase transfer catalysts are tri-C _{8-10 -alkylmethylammonium} chloride, tetrabutylammonium bromide, hexadecyltrimethylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium chloride, or tetrabutylammonium sulfide. Hydrogen salt. In a preferred embodiment, tetrabutylammonium hydrogen sulfide is used as the phase transfer catalyst.

In the present invention, preferred sulfonate compounds of formula (IV) are those wherein the sulfonate (IV) is mesylate (R ₁ = methyl), besylate (R ₁ = phenyl), or tosylate (R ₁ = 4-methylphenyl). is there. The most preferred sulfonate (IV) is mesylate.

  The compound of formula (III) can be converted to its salt, which can be converted to the free compound by methods known in the art.

  Amide compounds of formula (II) can be prepared from cyano compounds of formula (III) by hydrolysis as free bases or as salts. Preferably, the compound of formula (II) is obtained from the compound of formula (III) as the free base. For example, hydrolysis can be achieved by using mild conditions and / or by reducing the reaction time. The conditions for carrying out the hydrolysis can be easily determined by a person skilled in the art by routine tests. For example, the hydrolysis can be performed using the same reaction conditions as in Example 9 except that the reaction time is reduced, except that the cyano compound is hydrolyzed to montelukast, and then the amide compound. Isolate (II).

The last step of the process is a hydrolysis reaction. The compound of formula (II) can be hydrolyzed to obtain montelukast. The hydrolysis reaction can also be carried out directly from the cyano compound (III) as the free base or salt to obtain montelukast. Preferably, the hydrolysis of the compound of formula (II) or the compound of formula (III) as free base or salt is carried out with a base. Preferred bases are alkali metal hydroxides or alkaline earth metal hydroxides. More preferably, the base is sodium hydroxide, potassium hydroxide or lithium hydroxide. Most preferred is sodium hydroxide. The reaction can be carried out in various solvent systems. Preferably, the solvent system is a solvent mixture comprising a C ₁ -C ₄ alcohol and water. Preferably, the C ₁ -C ₄ alcohol is ethanol or isopropanol. Most preferred is ethanol. Typically, the hydrolysis of cyano compound (III) to montelukast (I) is carried out at reflux temperature and is essentially complete within 24 hours.

Other suitable solvent systems can be a two-phase solvent mixture containing water and a suitable organic solvent that is either immiscible or poorly miscible in water, optionally with a phase transfer catalyst. Preferably, the organic solvent is a (C ₆ -C ₈ ) aromatic hydrocarbon. Most preferred is toluene. Suitable phase transfer catalysts include, for example, quaternary ammonium salts, particularly tetrabutylammonium bromide, tri-C ₈ -C ₁₀ -alkylmethylammonium chloride, methyltrioctylammonium chloride, or hexadecyltrimethylammonium chloride. . The hydrolysis can be carried out at a temperature between room temperature and reflux temperature. Typically, under these reaction conditions, hydrolysis of the cyano compound (III) to montelukast (I) is carried out at 120 ° C. and is essentially complete within about 7 days.

  Separation of the crude montelukast can be achieved by diluting the crude compound with toluene, washing the solution with aqueous acetic acid followed by water at room temperature and then evaporating the solvent. The resulting montelukast can be purified by several methods such as aqueous acid-base extraction or recrystallization.

  The free acid of montelukast obtained by the method of the present invention may be converted into a pharmaceutically acceptable salt by a known method described in the art, or the salt may be converted into a free acid compound. Good. In addition, the salt of montelukast can be separated from the hydrolysis reaction. That is, montelukast free acid is not separated.

  The sulfonate compound of formula (IV) is prepared from the alcohol of formula (V) by reaction with the corresponding sulfonyl chloride. This reaction is carried out in a suitable solvent at a temperature ranging from −20 ° C. to room temperature in the presence of a tertiary amine. Preferably the reaction is carried out at a low temperature. Common solvents for the reaction include chlorine-containing solvents such as methylene chloride, or 1,2-dichloroethylene, aromatic hydrocarbons such as toluene or xylene, and dimethylformamide. Examples of suitable tertiary amines are diisopropylethylamine and triethylamine.

  Preparation of an alcohol of formula (V) as a free base or salt from a compound of formula (VI) involves reacting with a methylmagnesium halide, such as methylmagnesium chloride or methylmagnesium bromide, optionally in the presence of cerium chloride. By reacting with methyllithium in the presence of a suitable solvent. Examples of suitable solvents include ethers such as tetrahydrofuran, or aromatic hydrocarbons such as toluene or xylene, or mixtures thereof. Preferably the reaction is carried out at a temperature between -78 ° C and 20 ° C, more preferably at -20 ° C.

  The alcohol of formula (V) can be converted to its salt, which can be converted to the free compound by methods known in the art. For example, citrate salts are prepared by reacting citric acid with a compound of formula (V) as the free base in the presence of a suitable solvent.

  Compounds of formula (VI) as free bases or salts can be prepared from known compounds of formula (VII), the latter being in a suitable solvent such as dimethylformamide, dimethyl sulfoxide, dichloromethane, toluene or tetrahydrofuran. Reaction with a compound of formula (VIII) in the presence of a base such as cesium carbonate, sodium hydroxide and lithium-bis (trimethylsilyl) amide. Preferably the reaction is carried out at a temperature of -10 ° C to 60 ° C, more preferably 0-5 ° C.

  The compound of formula (VI) can be converted to its salt, which can be converted to the free compound by methods known in the art. For example, oxalate salts are prepared by reacting oxalic acid with a compound of formula (VI) as the free base in the presence of a suitable solvent.

のメチル-２-((Ｓ)-３-(３-((Ｅ)-２-(７-クロロキノリン-２-イル)ビニル)フェニル)-３-ヒドロキシプロピル)ベンゾアートと塩化メタンスルホニル又は塩化トルエンスルホニルを反応させ、メチル-２-((Ｓ)-３-(３-(Ｅ)-(２-(７-クロロキノリン-２-イル)ビニル)フェニル)-３-[(メチルスルホニル)オキシ]プロピル)ベンゾアート又は対応するトシレートを形成することを含む。同様に、式(ＶＩＩ)のベシレートは、対応する塩化ベンゼンスルホニルから得ることができる。 The compound of formula (VII) may be prepared according to known methods described in US2005107612. The method described in this document has the formula (IX)

Of methyl-2-((S) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-hydroxypropyl) benzoate and methanesulfonyl chloride or chloride Toluenesulfonyl is reacted with methyl-2-((S) -3- (3- (E)-(2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-[(methylsulfonyl) oxy ] Propyl) benzoate or the corresponding tosylate. Similarly, the besylate of formula (VII) can be obtained from the corresponding benzenesulfonyl chloride.

Compounds of formula (VIII) can be prepared from 5,7-dioxa-6-thiaspiro [2.5] octane-6-oxide according to the process summarized in Scheme 1.

A process for preparing a compound of formula (VIII) comprises reacting a compound of formula (XI) with potassium ethanethioate to obtain a compound of formula (X). Typically, such reactions are performed with an excess of potassium ethanethioate in a suitable solvent. Examples of suitable solvents include dimethyl sulfoxide, dimethylformamide, ethyl acetate, acetonitrile or mixtures thereof. Preferably the reaction is carried out at a temperature from room temperature to 70 ° C. After separating the compound of the formula (X), the compound of the formula (VIII) can be obtained by hydrolysis using an acid or a basic catalyst. Examples of suitable acids are hydrochloric acid, sulfuric acid, acetic acid and formic acid. Examples of suitable bases are alkali or alkaline earth metal hydroxides, carbonates, and alkoxides. Specific examples of suitable solvents are (C ₁ -C ₆ ) alcohols, (C ₆ -C ₈ ) aromatic hydrocarbons, dimethylformamide, dimethyl sulfoxide, or mixtures thereof.

  The best conditions for carrying out the method of the invention will vary depending on parameters considered by those skilled in the art, such as starting materials, molar ratios, temperatures, and the like. Such reaction conditions can be readily determined by one skilled in the art using routine testing and the teachings of the examples contained in this document.

  Throughout this specification and the claims, the term “comprising” and variations of the term are not intended to exclude other technical features, additives, ingredients or steps. The abstract of this application is incorporated herein by reference. Additional objects, advantages and features of the present invention will become apparent to those skilled in the art upon review of this specification or may be learned from practice of the invention. The following examples are provided for purposes of illustration and are not intended to limit the invention.

Example 1: Preparation of S- (1- (hydroxymethyl) cyclopropyl) methylethanethioate (X) 200 g of 5,7-dioxa-6-thiaspiro [2.5] octane-6-oxide Dissolved in 2 liters of dimethyl sulfoxide and 308 g of potassium ethanethioate was poured into the solution. The suspension was then heated at 40 ^° C. for 5 hours. As soon as the reaction was complete, a combination of 3.6 liters of ethyl acetate and 3.6 liters of water was added. The organic phase was separated, washed with water and concentrated to dryness. 200 g of S- (1- (hydroxymethyl) cyclopropyl) methyl ethanethioate was recovered. Yield: 78% corrected by GC. ¹ H NMR (400 MHz, CDCl ₃ ): 3.45 (2H, d, J: 6.4 Hz); 3.01 (2H, s); 2.53 (OH, broad triplet, J: 6.4 Hz) ); 2.39 (3H, s); 0.54 (4H, m).

Example 2: Preparation of (1- (mercaptomethyl) cyclopropyl) methanol (VIII) 200 g of S- (1- (hydroxymethyl) cyclopropyl) methylethanethioate was dissolved in 2 liters of methanol. Then 111 ml of concentrated HCl was added under a nitrogen atmosphere and the solution was stirred for 10 at room temperature. The solvent is distilled and the residue is redissolved in 1.5 liters of dimethylformamide and 2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl ) Phenyl) -3-(((1- (hydroxymethyl) cyclopropyl) methyl) sulfanyl) propyl) methyl benzoate was used. Yield: 100%. ¹ H NMR (400 MHz, CDCl ₃ ): 3.57 (2H, s); 2.63 (2H, d, J: 8.0 Hz); 2.45 (OH, broad signal); 1.43 (SH , t, J: 8.0 Hz); 0.52 (4H, m).

Example 3: 2-((S) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-[(methylsulfonyl) oxy] propyl) benzoic acid Preparation of Methyl Acid (R ₂ : CH ₃ VII) 12.1 ml of diisopropylethylamine was added to 120 ml of dichloromethane in 24.5 g of 2-((S) -3- (3-((E) -2- ( Pour into a stirred solution containing 7-chloroquinolin-2-yl) vinyl) phenyl) -3-hydroxypropyl) methyl benzoate. The mixture was cooled to −20 ° C. and 5 ml of mesyl chloride was added slowly. As soon as the reaction was complete, the crude solution was washed successively with 120 ml of 10% aqueous NaHCO ₃ solution and 120 ml of water. Finally, the solvent was distilled to give 29 g of the title compound. The product was redissolved in 290 ml dimethylformamide and used as a solution in the next step. Yield: 100%.

Example 4: 2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxymethyl) cyclo Preparation of methyl (VI) propyl) methyl) sulfanyl) propyl) benzoate A solution of 19 g (1- (mercaptomethyl) cyclopropyl) methanol in 190 ml dimethylformamide was cooled to 0 ° C. Then 52 g of Cs ₂ CO ₃ was added in one portion. After 10 minutes, the solution obtained from the previous example was added and the suspension was kept at the same temperature for 18 hours. Finally, a mixture of 380 ml ethyl acetate and 380 ml water was poured into the crude solution. The organic phase was washed with 380 ml water and concentrated to dryness. 30 g of brown oil was recovered. Yield: 86% corrected after HPLC analysis. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.38 (1H, d, J: 8.4 Hz); 8.00-7.26 (14 H, m); 4.50 (OH, t, J: 5.4 Hz); 3.92 (1 H, t, 7.2 Hz); 3.76 (3 H, s); 3.33 (1 H, dd, J: 11.0 Hz, 5.4 Hz); 3.25 ( 1H, dd, J: 11.0 Hz, 5.4 Hz); 2.98-2.88 (1H, m); 2.83-2.74 (1H, m); 2.52 (1H, d, J : 22.7 Hz); 2.39 (1H, d, J: 12.7 Hz); 2.10 (2H, m); 0.46-0.18 (4H, m).

Example 5: 2- (2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxy Preparation of methyl) cyclopropyl) methyl) sulfanyl) propyl) phenyl) propan-2-ol (V) The product obtained in the previous example was dissolved in 300 ml of tetrahydrofuran. The mixture was cooled to 0 ° C. and 307 ml of a 1.4M solution of methylmagnesium bromide was added under a nitrogen atmosphere. The reaction was held at 0 ° C. for 18 hours. Then 400 ml of a 2M aqueous solution of acetic acid was added slowly followed by 400 ml of ethyl acetate. The organic phase was washed successively with 400 ml 10% aqueous NaHCO ₃ and 400 ml water. Finally, the solvent was distilled off to obtain 30 g of crude compound. Yield: 81% corrected after HPLC analysis. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.39 (1H, d, J: 8.6 Hz); 8.00-7.06 (14 H, m); 4.91 (OH, s); 4 .51 (OH, t, J: 5.5 Hz); 3.99 (1 H, t, 7.3 Hz); 3.34 (1 H, dd, J: 11.0 Hz, 5.5 Hz); 3.26 ( 1H, dd, J: 11.0 Hz, 5.5 Hz); 3.05 (1 H, m); 2.74 (1 H, m); 2.54 (1 H, d, J: 12.7 Hz); 41 (1H, d, J: 12.7 Hz); 2.15 (2H, m); 1.44 (6H, s); 0.45-0.36 (2H, m); 0.33-0. 22 (2H, m).

Example 6: 2- (2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxy Preparation of methyl) cyclopropyl) methyl) sulfanyl) propyl) phenyl) propan-2-ol (V) 1.3 g of anhydrous cerium chloride was stirred in 10 ml of anhydrous tetrahydrofuran at room temperature for 18 hours. The suspension was then cooled to −20 ° C. and 1.5 ml of a 3M solution of methylmagnesium chloride was added under a nitrogen atmosphere. After a predetermined time, 2.5 ml of a tetrahydrofuran solution containing 0.5 g of the product obtained in Example 4 was added. The mixture was stirred at the same temperature for 18 hours and 10 ml of a 2M solution of acetic acid was added slowly followed by 10 ml of ethyl acetate. The organic phase was washed successively with 10 ml of 10% aqueous NaHCO ₃ and 10 ml of water. Finally, the solvent was distilled off to obtain 0.5 g of crude compound. Yield: 80% corrected after HPLC analysis.

Example 7: (R, E)-(1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane-2) Preparation of -yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) methyl methanesulfonate (IV with R ₁ = CH ₃ ) 6.5 ml of diisopropylethylamine in 16 ml of 2- (2 -((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-(((1- (hydroxymethyl) cyclopropyl) methyl) sulfanyl The solution was poured into a stirred solution containing) propyl) phenyl) propan-2-ol. The mixture was cooled to −20 ° C. and 2.7 ml of mesyl chloride was added slowly. The mixture was stirred at the same temperature for 1 hour and then washed twice with 300 ml of water. The solvent was distilled and 18 g of crude compound was recovered. Yield: 100%. ¹ H NMR (400 MHz, DMSO-d6): 8.41 (1H, d, J: 9.6 Hz); 8.02-7.03 (14H, m); 4.91 (OH, s); 4.02 (1H, t, J: 7.1 Hz); 3.12 (3H, s); 3.09-3.02 (1H, m); 2.78-2. 71 (1 H, m); 2.54 (1 H, d, J: 13.2 Hz); 2.46 (1 H, d, J: 13.2 Hz); 2.15 (2 H, m); 1.43 ( 3H, s); 1.42 (3H, s); 0.68-0.45 (4H, m).

Example 8: (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane) Preparation of -2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetonitrile (III) The crude compound obtained in the previous example was dissolved in 180 ml dimethylformamide and 2.1 g sodium cyanide was Added once to the solution. After stirring for 18 hours at 60 ° C., 270 ml of ethyl acetate was poured into the mixture which had been warmed to room temperature. Subsequently, it was washed twice with 270 ml of water, and the solvent was distilled to obtain 14 g of a crude compound. Yield: 75% corrected after HPLC analysis. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.39 (1H, d, J: 8.6 Hz); 8.00-7.05 (14 H, m); 4.90 (OH, s); 4 .04 (1H, t, J: 7.2 Hz); 3.06 (1H, m); 2.76 (1H, m); 2.67 (1H, m); 2.33 (1H, m); 2.30 (2H, s); 2.13 (2H, m); 1.43 (6H, s); 0.59-0.43 (4H, m).

Example 9: (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane) Preparation of -2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetamide (II) 1.8 g of the crude compound obtained in Example 8 was dissolved in 3.6 ml of toluene. Then 3.6 ml of water was added followed by 14.7 g of sodium hydroxide and 0.44 g of tetrabutylammonium bromide. The mixture was stirred at 120 ° C. for 30 hours. After this period, 10 ml of toluene and 10 ml of water were added to the reaction solution previously cooled to room temperature. The organic phase was separated and washed with 10 ml water. Finally, the solvent was distilled and the crude compound was purified by standard methods and 77 mg of the title compound was recovered. Yield: 6%. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.41 (1H, d, J: 8.6 Hz); 8.03-7.07 (15 H, m); 6.74 (1 H, s); 4 .91 (OH, s); 4.02 (1 H, t, J: 7.3 Hz); 3.04 (1 H, m); 2.75 (1 H, m); 2.57 (1 H, d, J : 13.3 Hz); 2.45 (1H, d, J: 13.3 Hz); 2.16 (4H, m); 1.43 (6H, s); 0.50-0.27 (4H, m) )

Example 10: 2- (1-((((R) -1- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2 Preparation of -hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid (Montelukast free acid) 5.2 g of the crude compound obtained in Example 8 was dissolved in 10 ml of toluene. . Then 10 ml water was added followed by 14.7 g sodium hydroxide and 0.44 g tetrabutylammonium bromide. The mixture was stirred at 120 ° C. for 7 days. After this period, 10 ml of toluene and 10 ml of water were added to the reaction solution previously cooled to room temperature. The organic phase was separated and washed with 10 ml acetic acid and 10 ml water. Finally, the solvent was distilled and 4.6 g of crude compound was recovered which could be purified by standard methods if necessary. Yield: 83%. ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.02 (1H, s); 8.39 (1H, d, J: 8.6 Hz); 8.01-7.04 (14H, m); 4 90 (OH, s); 4.00 (1 H, t, J: 7.3 Hz); 3.05 (1 H, m); 2.76 (1 H, m); 2.56 (1 H, d, J : 22.9 Hz); 2.47 (1H, d, J: 12.9 Hz); 2.32 (2H, s); 2.16 (2H, m); 1.44 (6H, s); 52-0.33 (4H, m). IR (KBr) = 3573.1, 3436.9, 2919.2, 176.9, 1608.9, 1499.9, 1408.8, 1315.7, 1223.9, 1201.6, 1173.0, 1148 0.0,1134.9,1074.8,965.9,950.8,933.2,863.6,842.7,766.0 cm ⁻¹ .

Example 11: 2- (1-((((R) -1- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2 Preparation of -Hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetic acid (Montelukast free acid) 1.05 g of sodium hydroxide was added to ethanol: water (96: 4, v / v). To a 5 ml mixture was added 1 g of (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxy The solution was poured into a solution containing propan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetonitrile. The resulting suspension was stirred at reflux temperature for 15 hours. After this period, the reaction mixture was cooled to room temperature and diluted with 10 ml of toluene. Then 20 ml of a 2M aqueous solution of acetic acid was slowly added and the organic phase was separated and washed twice with 10 ml of water. Finally, the solvent was distilled and 0.9 g of crude compound was recovered which could be purified by standard methods if necessary. Yield: 91%.

Example 12: 2- (1-((((R) -1- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2 Preparation of 2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) sodium acetate (Montelukast sodium) 2.6 g of Montelukast free acid was dissolved in 26 ml of toluene and 0.5 M NaOH in methanol. 8.9 ml of the solution was slowly added at room temperature. The mixture was stirred for 1 hour and the solvent was removed under vacuum to give a residue. Then heptane (24 ml) was added to the well stirred solution of the residue in 4 ml ethyl acetate at room temperature over 30 minutes. Two hours after the addition, the off-white solid was filtered under a nitrogen atmosphere and washed with 5 ml of heptane. The wet product was dried under vacuum at 70-80 ° C. for 2 days, yielding 2.7 g of montelukast sodium in amorphous solid form. Yield: 100%. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.38 (1H, d, J: 8.6 Hz); 8.02-7.04 (14H, m); 5.19 (OH, s); 4 .01 (1 H, t, J: 7.2 Hz); 3.08 (1 H, m); 2.72 (1 H, m); 2.69 (1 H, d, J: 12.4 Hz); 2.54 (1H, d, J: 12.4 Hz); 2.22 (1H, m); 2.10 (1H, d, J: 14.2 Hz); 2.10 (1H, m); 1.96 (1H , d, J: 14.2 Hz); 1.45 (3H, s); 1.44 (3H, s); 0.46-0.32 (2H, m); 0.28-0.15 (2H) , m).

Example 13: 2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxymethyl) cyclo Preparation of oxalate of methyl propyl) methyl) -sulfanyl) propyl) benzoate (oxalate of compound (VI)) To 2.0 liters of toluene, 338 g (0.61 mol) of 2-((R)- 3- (3-((E) -2- (7-Chloroquinolin-2-yl) vinyl) phenyl) -3-(((1- (hydroxymethyl) cyclopropyl) methyl) sulfanyl) propyl) methyl benzoate A solution containing 75 g (0.60 mol) of oxalic acid dihydrate in 1.0 liter of acetonitrile was slowly added at room temperature. The resulting suspension was stirred for 10 hours at room temperature. The solid was filtered and washed several times with a mixture of toluene / acetonitrile: 2/1 (v / v). The wet solid was dried at 25 ° C. under vacuum. 304 g of a yellow solid was obtained. Yield: 78%. DSC: 121.6 ° C (peak). ¹ H NMR (400 MHz, DMSO-d6): 8.42 (1H, d, J: 8.6 Hz); 8.00-7.28 (14 H, m); 3.92 (1 H, t, 7.3 Hz) ); 3.76 (3H, s); 3.31 (1H, d, J: 11.0 Hz); 3.25 (1H, d, J: 11.0 Hz); 2.98-2.90 (1H) , m); 2.82-2.75 (1 H, m); 2.52 (1 H, d, J: 12.7 Hz); 2.39 (1 H, d, J: 12.7 Hz); 2.14 -2.08 (2H, m); 0.43-0.19 (4H, m). DSC measurements were performed using a DSC Mettler Toledo DSC 822 from 25.0 ° C. to 150.0 ° C. in a perforation pan with a scan rate of 5 ° C./min.

Example 14: 2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxymethyl) cyclo Preparation of Propyl) methyl) sulfanyl) propyl) methyl benzoate (VI) 283 g of the oxalate salt prepared in Example 13 was suspended in 1.7 liters of toluene and 1.7 liters of water. 35% aqueous hydrochloric acid was slowly added to the previous mixture until a pH of 6.5 was obtained. The organic phase was separated and washed with water. Finally the solvent was distilled under vacuum. 243 g of oil was obtained. Yield: 100%.

Example 15: 2- (2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxy Preparation of methyl) cyclopropyl) methyl) sulfanyl) propyl) phenyl) propan-2-ol citrate (citrate of compound (V)) In 910 ml of toluene, 92.5 g of 2- (2-((R)) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-(((1- (hydroxymethyl) cyclopropyl) methyl) sulfanyl) propyl) phenyl) A solution containing propan-2-ol (HPLC: 78 area%) was heated to 55 ° C. Then 34.8 g of citric acid monohydrate was added in one portion. After 1 hour of stirring at the same temperature, the mixture was gradually cooled to 20 ° C. over 2 hours and stirred at this temperature for over 2 hours. Finally, the suspension was filtered under vacuum and the cake was washed twice with 100 ml of toluene. The product was used as a wet solid in the next step. (HPLC: 97 area%). ¹ H NMR (400 MHz, DMSO-d6): 12.38 (2H, s); 8.39 ( ¹ H, d, J: 8.6 Hz); 8.02-7.11 (14H, m); 4 90 (OH, s); 4.51 (OH, s); 3.99 (1 H, t, J: 7.3 Hz); 3.34 (1 H, d, J: 11.0 Hz); 3.27 (1H, d, J: 11.0 Hz); 3.06 (1 H, td, J: 12.3 Hz; J: 4.9 Hz); 2.77 (2H, d, J: 15.4 Hz); 73 (1 H, m); 2.66 (2 H, d, J: 15.4 Hz); 2.54 (1 H, d, J: 12.7 Hz); 2.41 (1 H, d, J: 12.7 Hz) 2.17 (2H, m); 1.44 (6H, s); 0.44-0.36 (2H, m); 0.32-0.22 (2H, m). IR (KBr) = 3411, 3052, 2970, 2922, 2593, 1727, 1632, 1599, 1488, 1437, 1409, 1376, 1318, 1223, 1208, 1153, 1080, 1026, 961, 927, 861, 840, 760 729,694,598,471 cm ⁻¹ .

Example 16: 2- (2-((R) -3- (3-((E) -2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3-((((1- (hydroxy Preparation of methyl) cyclopropyl) methyl) sulfanyl) propyl) phenyl) propan-2-ol (V) The wet solid obtained in Example 15 was partitioned between 800 ml toluene and 800 ml 5% aqueous NaHCO ₃ solution. The organic phase was separated, washed with 800 ml of water and concentrated to dryness on a rotary evaporator at 30 ° C. under vacuum. 29.7 g of a pale yellow solid was recovered. Overall yield over two steps: 39% (HPLC: 96 area%).

Example 17: (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane) Preparation of -2-yl) phenyl) propyl) sulfanyl) methyl) cyclo-propyl) acetonitrile (III) 5 ml of water was added to 10 g of (R, E)-(1-((1- (3- (2- ( 7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropan-2-yl) phenyl) propylthio) methyl) cyclopropyl) methyl methanesulfonate; followed by 0.5 g of tetrabutyl To a solution of 96 g of toluene containing ammonium hydrogen sulfide and 0.85 g of sodium cyanide. The mixture was stirred at 60 ° C. for 20 hours. Then it was cooled to room temperature and the organic phase was washed 3 times with 100 ml water. Finally, the obtained toluene solution was concentrated to dryness on a rotary evaporator at 30 ° C. under vacuum. 9.5 g was obtained.

General example: (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane- Preparation of salt of 2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetonitrile (salt of compound (III)) in 3.5 ml of toluene, 0.5 g (8.82 mmol) of (R, E)- 2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropan-2-yl) phenyl) propyl) sulfanyl To a solution containing) methyl) cyclopropyl) acetonitrile, a solution of 8.82 mmol acid in acetonitrile or tetrahydrofuran was slowly added at room temperature. The solvent was distilled to give the theoretical amount of salt as a yellow solid.
The general examples were repeated using the corresponding acids shown in the examples below.

Example 18: Preparation of oxalate salt of compound (III) using oxalic acid Yield: 100%; IR (KBr) (cm ^-1 ): 3420,2970,2925,1719,1626,1600,1486,1408 , 1205, 1157, 1080, 762, 695; ¹ H RMN (400 MHz, DMSO-d6): 8.41 (1H, d, J: 8.7 Hz); 8.0-7.1 (14H, m); 4.04 (1H, t, 7.3 Hz); 3.1 (1H, m); 2.8 (1H, m); 2.63 (2H, s); 2.51 (2H, half-deuterated) (Under DMSO)); 2.2 (2H, m); 1.44 (3H, s); 1.43 (3H, s); 0.60-0.40 (4H, m).

Example 19: Preparation of malate of compound (III) using L-(-)-malic acid Yield: 100%; IR (KBr) (cm-1): 3436, 2976, 2930, 1721, 1628 , 1607, 1498, 1409, 1161, 1078, 761, 696; ¹ H RMN (400 MHz, DMSO-d6): 12.41 (1 H, wide area); 8.40 (1 H, d, J 8.69 Hz); 8 4.0-1 (14H, m); 4.91 (1H, s); 4.26 (1H, dd, J 7.83 Hz, J 4.78 Hz); 4.04 (1H, t, 7. 35 Hz); 3.11-3.01 (1 H, m); 2.80-2.70 (1 H, m); 2.61 (1 H, dd, J 15.66 Hz, J 4.80 Hz); 51 (2H, under semi-deuterated DMSO), 2.44 (1H, dd, J 15.66Hz, J 7.84Hz); 2.26-2.10 (2H, m); 1.44 (3H, s); .43 (3H, s); 0.60-0.40 (4H, m).

Example 20: Preparation of tartrate salt of compound (III) using L-(+)-tartaric acid Yield: 100%; IR (KBr) (cm-1): 3401, 2970, 2927, 1726, 1626, 1605 , 1487, 1408, 1205, 1130, 1080, 762, 696; ¹ H RMN (400 MHz, DMSO-d6): 12.68 (1 H, broad); 8.41 (1 H, d, J: 8.64 Hz); 8.04-7.04 (14H, m); 4.91 (1H, s); 4.31 (2H, s); 4.04 (1H, t, J 7.34 Hz); 3.12-3 .00 (1H, m); 2.81-2.70 (1H, m); 2.64 (2H, s); 2.51 (2H, under semi-deuterated DMSO); 2.26-2. 07 (2H, m); 1.44 (3H, s); 1.43 (3H, s); 0.60-0.40 (4H, m).
The following salts of compound (III): maleate, fumarate, succinate, benzoate, 4-hydroxymandelate, citrate, and mandelate were prepared from the corresponding acids using the methods of general examples.

Example 21: (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane) Preparation of oxalate salt of -2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetonitrile (oxalate salt of compound (III)) In 21.5 ml of toluene, 3.14 g (5.53 mmol) of ( R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropan-2-yl) To a solution of phenyl) propyl) sulfanyl) methyl) -cyclopropyl) acetonitrile, a solution of 0.68 g (5.42 mmol) of oxalic acid dihydrate in 10 ml of acetonitrile was added at room temperature. The solution was concentrated under vacuum to half of the original volume and stirred at room temperature overnight. The resulting solid was filtered and dried under vacuum. 2.71 g (yield: 71%) of a yellow solid was obtained. ¹ H NMR (400 MHz, DMSO-d6): 8.41 (1H, d, J: 8.7 Hz); 8.0-7.1 (14 H, m); 4.04 (1 H, t, 7.3 Hz) 3.1 (1H, m); 2.8 (1H, m); 2.63 (2H, s); 2.51 (2H, under semi-deuterated DMSO); 2.2 (2H, m) ); 1.44 (3H, s); 1.43 (3H, s); 0.60-0.40 (4H, m). IR (KBr) = 3420, 2970, 2925, 1719, 1626, 1600, 1486, 1408, 1205, 1157, 1080, 762, 695 cm- ¹ .

Example 22: (R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropane) Preparation of Benzenesulfonate of -2-yl) phenyl) propyl) sulfanyl) methyl) cyclopropyl) acetonitrile (benzenesulfonate of compound (III)) To 6 ml of toluene, 1.0 g (1.76 mmol) of ( R, E) -2- (1-((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxypropan-2-yl) To a solution of phenyl) propi) sulfanyl) methyl) -cyclopropyl) acetonitrile, a solution of 303 g (1.73 mmol) of benzenesulfonic acid 90% in 0.6 ml acetonitrile was added at room temperature. The solution was stirred overnight at room temperature. The resulting solid was filtered and dried under vacuum. 0.96 g (yield: 75%) of a yellow solid was obtained. ¹ H NMR (400 MHz, DMSO-d6): 8.74 (1 H, d, J: 8.7 Hz); 8.27-7.04 (19 H, m); 4.07 (1 H, t, 7.3 Hz) 3.1 (1H, m); 2.8 (1H, m); 2.63 (2H, s); 2.51 (2H, under semi-deuterated DMSO); 2.2 (2H, m) ); 1.44 (3H, s); 1.43 (3H, s); 0.61-0.41 (4H, m). IR (KBr) = 3430, 3050, 2910, 1625, 1600, 1480, 1230, 1150, 1125, 1020, 990, 690, 610 cm-1.

Claims (33)

A process for preparing montelukast (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof comprising a hydrate comprising:
(a) Formula (IV)

Wherein R ₁ is a group selected from the group consisting of (C ₁ -C ₄ ) -alkyl, phenyl, and phenyl mono- or di-substituted by a (C ₁ -C ₄ ) -alkyl group. is there)
Is reacted with an alkali metal cyanide to give a compound of formula (III)

And the compound (III) is isolated as the free base or a salt thereof;
(b) In some cases, the compound of formula (III) obtained in step (a) is converted to formula (II)

Hydrolyzing under the reaction conditions leading to the compound, separating the compound (II) from the reaction medium;
(c) subjecting the compound obtained in step (a) or step (b) to a hydrolysis reaction under the reaction conditions leading to montelukast (I);
(d) optionally treating montelukast (I) with a pharmaceutically acceptable base to form the corresponding salt;
A preparation method comprising the steps.   The process according to claim 1, wherein the compound of formula (III) is isolated as the free base. The preparation method according to claim 1 or 2, wherein R ₁ is selected from the group consisting of methyl, phenyl, and 4-methylphenyl. The preparation method according to claim 3, wherein R ₁ is methyl.   The preparation method according to any one of claims 1 to 4, wherein the alkali metal cyanide is selected from sodium cyanide and potassium cyanide.   The preparation method according to any one of claims 1 to 5, wherein step (a) is carried out in the presence of a phase transfer catalyst. The phase transfer catalyst comprises tri-C8-10- _{alkylmethylammonium} chloride, tetrabutylammonium bromide, hexadecyltrimethylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium chloride, and tetrabutylammonium hydrogen sulfide. The preparation method according to claim 6, which is selected from:   The preparation method according to claim 7, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfide.   The preparation method according to any one of claims 1 to 8, wherein the hydrolysis reaction in steps (b) and (c) is carried out using a base.   The preparation method according to claim 9, wherein the base is sodium hydroxide.   The preparation method according to claim 9 or 10, wherein the hydrolysis is carried out in a mixture containing water and an organic solvent, optionally in the presence of a phase transfer catalyst. The preparation method according to claim 11 organic solvent is selected from the group consisting of C ₁ -C ₄ alcohol and toluene. In a further step, the formula (V)

The compounds, either reacted with sulphonyl chlorides of the formula Cl-SO ₂ -R ₁ wherein R ₁ has the same meaning as described in claim 1 of claims 1 to give a compound of formula (IV) 12 of The preparation method according to one item. In a further step, the formula (VI)

Is reacted with a Grignard reagent selected from methyllithium and methylmagnesium halide, optionally in the presence of cerium chloride, to obtain a compound of formula (V), wherein (V) is a free base or a salt thereof. The preparation method according to claim 13, which is isolated as follows.   The process according to claim 14, wherein the compound of formula (V) is separated as the free base.   The method according to claim 14 or 15, wherein the methylmagnesium halide is methylmagnesium chloride. In a further step, R ₂ is a group selected from the group consisting of (C ₁ -C ₄ ) -alkyl, phenyl, and phenyl mono- or di-substituted by a (C ₁ -C ₄ ) -alkyl group. A formula (VII)

In the presence of a base of formula (VIII)

17. The preparation method according to any one of claims 14 to 16, wherein the compound of the formula (VI) is obtained by reacting with the compound of the above, and the compound (VI) is separated as a free base or a salt thereof.   18. A process according to claim 17, wherein the compound of formula (VI) is isolated as the free base.   The process according to claim 17, wherein compound (VI) is isolated as an oxalate. R ₂ is methyl, phenyl, and preparation method according to any one of claims 17 to 19 which is selected from the group consisting of 4-methylphenyl. The preparation method according to claim 20 R ₂ is methyl.   The preparation method according to any one of claims 17 to 21, wherein the base is selected from the group consisting of cesium carbonate, sodium hydroxide, and lithium-bis (trimethylsilyl) amide.   The preparation method according to claim 22, wherein the base is cesium carbonate. Wherein R ₁ is a group selected from the group consisting of (C ₁ -C ₄ ) -alkyl, phenyl, and phenyl mono- or di-substituted by a (C ₁ -C ₄ ) -alkyl group (IV)

Compound. R ₁ is The compound of claim 24 selected from methyl, phenyl, and 4-methylphenyl. A compound according to claim 25 R ₁ is methyl. The following formula (V)

Compound.   A salt of a compound of formula (V).   30. The compound of claim 28, wherein the salt is citrate. The following formula (VI)

Compound.   A salt of a compound of formula (VI).   32. The compound of claim 31, wherein the salt is an oxalate salt. Oxalate, L (-)-malate, L-(-)-tartrate, maleate, fumarate, succinate, benzoate, 4-hydroxymandelate, citrate, benzene Formula (III) selected from the group consisting of sulfonate and mandelate

Salt of the compound.